Acute exacerbations of chronic obstructive pulmonary disease (COPD), characterized by symptoms of worsening dyspnea, increased cough and sputum production, are troubling episodes for patients, leading them to seek medical care. Acute exacerbations are a major source of morbidity, mortality, and healthcare expenditure in COPD. Inhaled corticosteroids (ICS) are commonly prescribed for patients with severe COPD and have been shown to improve symptoms and reduce exacerbation risk. However, there is substantial inter- individual variation in the effects of ICS. The overarching hypothesis of this proposal is that clinical, imaging and genetic factors influence an individual COPD patient's response to ICS to prevent COPD exacerbations. The relevant genes can be identified by integrating genetic, genomic and epigenetic information. We propose to test this hypothesis in a clinical trial of ICS (budesonide, Pulmicort) or ICS/long acting beta-agonist combination (budesonide/ formoterol, Symbicort) in subjects with airway predominant COPD, nested within the COPDGene Study, a multicenter observational study of COPD. Specific Aim 1 will address the hypothesis that gene expression and DNA methylation differences in response to ICS treatment for 12 weeks can be identified in the peripheral blood of COPD patients. Aim 2 will address the hypothesis that genetic variation will influence gene expression levels and DNA methylation in the ICS-responsive genes from Aim 1. Aim 3 will address the hypothesis that clinical and imaging variables, as well as genetic variation in steroid-responsive genes, will affect exacerbation risk in COPD subjects using ICS. The integrative genomics approach we propose can limit the pharmacogenetics testing to a biologically-relevant gene set, reducing multiple testing concerns and improving our ability to identify genetic predictors of response to ICS to prevent acute exacerbations of COPD. The clinical, imaging, and genetic predictors of ICS response will be combined to construct a predictive model, making an important step towards a personalized genomics approach to COPD symptom management.